Recombinant viral vaccine

Abstract

The present invention concerns new recombinant viral vaccines. In particular the present invention provides combination products that comprise recombinant viral vectors and specific compounds able to improve the immune response raised in vivo by said recombinant viral vectors.

1 - 4 . (canceled) 
   
   
       5 . A recombinant viral vaccine comprising:
 (i) at least one recombinant poxviral vector expressing in vivo at least one heterologous nucleotide sequence; and   (ii) at least one 1H-imidazo[4,5-c]quinolin-4-amine derivative.   
   
   
       6 . The recombinant viral vaccine of  claim 5 , wherein said at least one heterologous nucleotide sequence encodes an antigen. 
   
   
       7 . A kit for vaccination, comprising:
 (i) a container comprising at least one recombinant poxviral vector expressing in vivo at least one heterologous nucleotide sequence; and   (ii) a container comprising at least one 1H-imidazo[4,5-c]quinolin4-amine derivative.   
   
   
       8 . The kit of  claim 7 , wherein said at least one heterologous nucleotide sequence encodes an antigen. 
   
   
       9 . The recombinant viral vaccine of  claim 5 , wherein said poxviral vector is a highly attenuated vaccinia virus strain. 
   
   
       10 . The recombinant viral vaccine of  claim 9 , wherein said highly attenuated vaccina virus strain is a highly attenuated vaccinia virus strain obtained from the Copenhagen or the Wyeth strain. 
   
   
       11 . The recombinant viral vaccine of  claim 5 , wherein said 1H-imidazo[4,5-c]quinolin-4-amine derivative is a compound defined by one of the following general formulae I-V: 
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R ii  is selected from the group consisting of straight or branched alkyl, hydroxyalkyl, acyloxyalkyl, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties selected, independently from one another, from the group consisting of C 1-4  alkyl moiety, C 1-4  alkoxy moiety and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than 6 carbon atoms; 
       R 21  is selected from the group consisting of hydrogen, C 1-8  alkyl moiety, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties selected, independently from one another, from the group consisting of C 1-4  alkyl moiety, C 1-4  alkoxy moiety and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than 6 carbon atoms; 
       and each R i  is selected, independently from one another, from the group consisting of hydrogen, C 1-4  alkoxy moiety, halogen and C 1-4  alkyl moiety, and n is an integer from 0 to 2, with the proviso that if n is 2, then said R 1  groups together contain no more than 6 carbon atoms; 
     
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R 12  is selected from the group consisting of straight or branched C 2-10  alkenyl and substituted straight or branched C 2-10  alkenyl, wherein the substituent is selected from the group consisting of straight or branched C 1-4  alkyl moiety and C 3-6  cycloalkyl moiety; and C 3-6  cycloalkyl moiety substituted by straight or branched C 1-4  alkyl moiety; and 
       R 22  is selected from the group consisting of hydrogen, straight or branched C 1-8  alkyl moiety, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties selected, independently from one another, from the group consisting of straight or branched C 1-4  alkyl moiety, straight or branched C 1-4  alkoxy moiety, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than 6 carbon atoms; 
       and each R 2  is selected, independently from one another, from the group consisting of straight or branched C 1-4  alkoxy moiety, halogen, and straight or branched C 1-4  alkyl moiety, and n is an integer from zero to 2, with the proviso that if n is 2, then said R 2  groups together contain no more than 6 carbon atoms; 
     
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R 23  is selected from the group consisting of hydrogen, straight or branched C 1-8  alkyl moiety, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties selected, independently from one another, from the group consisting of straight or branched C 1-4  alkyl moiety, straight or branched C 1-4  alkoxy moiety, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than 6 carbon atoms; 
       and each R 3  is selected, independently from one another, from the group consisting of straight or branched C 1-4  alkoxy moiety, halogen, and straight or branched C 1-4  alkyl moiety, and n is an integer from zero to 2, with the proviso that if n is 2, then said R 3  groups together contain no more than 6 carbon atoms; 
     
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R 14  is —CHR34R 44  wherein R 44  is hydrogen or a carbon-carbon bond, with the proviso that when R 44  is hydrogen R 34  is C 1-4  alkoxy moiety, C 1-4  hydroxyalkoxy moiety, C 2-10  1-alkynyl moiety, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R 44  is a carbon-carbon bond R 44  and R 34  together form a tetrahydrofuranyl group optionally substituted with one or more substituents selected, independently from one another, from the group consisting of hydroxy and C 1-4  hydroxyalkyl moities; 
       R 24  is selected from the group consisting of hydrogen, C 1-4  alkyl, phenyl, wherein the phenyl is optionally substituted by one or two moieties selected, independently from one another, from the group consisting of straight or branched C 1-4  alkyl moiety, straight or branched C 1-4  alkoxy moiety, and halogen; 
       and R 4  is selected from the group consisting of hydrogen, straight or branched C 1-4  alkoxy moiety, halogen, and straight or branched C 1-4  alkyl moiety; 
     
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R 15  is selected from the group consisting of hydrogen; straight or branched C 1-10  alkyl moiety and substituted straight or branched C 1-10  alkyl moiety, wherein the substituent is selected from the group consisting of C 3-6  cycloalkyl and C 3-6  cycloalkyl substituted by straight or branched C 1-4  alkyl moiety; straight or branched C 2-10  alkenyl and substituted straight or branched C 2-10  alkenyl moiety, wherein the substituent is selected from the group consisting of C 3-6  cycloalkyl and C 3-6  cycloalkyl substituted by straight or branched C 1-4  alkyl moiety; C 1-6  hydroxyalkyl; alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety contains one to about six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties selected, independently from one another, from the group consisting of C 1-4  alkyl moiety, C 1-4  alkoxy moiety, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; 
       R 25  is 
     
     
       
         
         
             
             
         
       
       wherein 
       R 35  is selected from the group consisting of C 1-4  alkoxy moiety, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms; C 1-4  haloalkyl moiety; alkylamido wherein the alkyl group contains one to about four carbon atoms; amino; amino substituted with C 1-4  alkyl or C 1-4  hydroxyalkyl; azido; C 1-4  alkylthio; 
       R 55  and R 45  are selected, independently from one another, from the group consisting of hydrogen, C 1-4  alkyl moiety, phenyl, wherein said phenyl is optionally substituted by one or two moieties selected, independently from one another, from the group consisting of straight or branched C 1-4  alkyl moiety, straight or branched C 1-4  alkoxy moiety, and halogen; and 
       R 5  is selected from the group consisting of hydrogen, straight or branched C 1-4  alkoxy moiety, halogen, and straight or branched C 1-4  alkyl containing moiety. 
     
   
   
       12 . The recombinant viral vaccine of  claim 5 , wherein said 1H-imidazo[4,5-c]quinolin-4-amine derivative is a compound defined by the following general formula VI: 
     
       
         
         
             
             
         
       
       or analogues, solvates or salts thereof, 
       wherein 
       R t  is selected from the group consisting of hydrogen, straight or branched C 1-4  alkoxy moiety, halogen, and straight or branched C 1-4  alkyl; 
       R u  is 2-methylpropyl or 2-hydroxy-2-methylpropyl; and 
       R v  is hydrogen, C 1-6  alkyl, or alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms. 
     
   
   
       13 . The recombinant viral vaccine of  claim 5 , wherein said heterologous nucleotide sequence encodes one or more of all or part of the HPV-E1, E2, E3, E4, E5, E6, E7, E8, L1, and L2 antigens. 
   
   
       14 . A method of enhancing an immune response to an antigen in a patient, said method comprising administering to said patient:
 (i) at least one recombinant viral vector expressing in vivo at least one heterologous nucleotide sequence encoding an antigen; and   (ii) at least one 1H-imidazo[4,5-c]quinolin-4-amine derivative;   thereby enhancing an immune response to said antigen.   
   
   
       15 . The method of  claim 14 , wherein said 1H-imidazo[4,5-c]quinolin-4-amine derivative is administered independently of and prior to administration of said recombinant viral vector. 
   
   
       16 . The method of  claim 14 , wherein said 1H-imidazo[4,5-c]quinolin-4-amine derivative and said recombinant viral vector are administered simultaneously. 
   
   
       17 . The method of  claim 14 , wherein said recombinant viral vector is a recombinant poxviral vector. 
   
   
       18 . The method of  claim 14 , wherein said heterologous nucleotide sequence encodes one or more of all or part of the HPV-E1 E2, E3, E4, E5, E6, E7, E8, LI, and L2 antigens.